V232M substitution restricts a distinct O-glycosylation of PLD3 and its neuroprotective function.

Neurobiol Dis 2019 Sep 20;129:182-194. Epub 2019 May 20.

Department of Brain Science, Asan Medical Center, Bio-Medical Institute of Technology (BMIT), University of Ulsan College of Medicine, Seoul, Republic of Korea; ADEL Institute of Science and Technology (AIST), ADEL, Inc., Seoul, Republic of Korea. Electronic address:

The link between Val232Met variant of phospholipase D3 (PLD3) and late-onset Alzheimer's disease (AD) is still obscure. While it may not affect directly the amyloid precursor protein function, PLD3 could be regulating multiple cellular compartments. Here, we investigated the function of wild-type human PLD3 (PLD3) and the Val232Met variant (PLD3) in the presence of β-amyloid (Aβ) in a Drosophila melanogaster model of AD. We expressed PLD3 in CNS of the Aβ-model flies and monitored its effect on the ER stress, cell apoptosis and recovery the Aβ-induced cognitive impairment. The expression reduced ER stress and neuronal apoptosis, which resulted in normalized antioxidative phospholipids levels and brain protection. A specific O-glycosylation at pT271 in PLD3 is essential for its normal trafficking and cellular localization. The V232 M substitution impairs this O-glycosylation, leading to enlarged lysosomes and plausibly aberrant protein recycling. PLD3 was less neuroprotective, and while, PLD3 expression enhances the lysosomal functions, V232 M attenuated PLD3's trafficking to the lysosomes. Thus, the V232 M mutation may affect AD pathogenesis. Further understanding of the mechanistic role of PLD3 in AD could lead to developing novel therapeutic agents.

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Source
https://linkinghub.elsevier.com/retrieve/pii/S09699961193012
Publisher Site
http://dx.doi.org/10.1016/j.nbd.2019.05.015DOI Listing
September 2019
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